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From: Contemporary Endocrinology: Androgen Excess Disorders in Women:
Polycystic Ovary Syndrome and Other Disorders, Second Edition Edited by: R. Azziz et al. © Humana Press Inc., Totowa, NJ
39
Weight Reduction and Lifestyle Modifiction in the Treatment of Androgen Excess
Manny Noakes, Lisa J. Moran, Grant D. Brinkworth, and Robert J. Norman
SUMMARY
Polycystic ovary syndrome (POCS) is a common disorder in women resulting in anovulation and reproduc- tive dysfunction. Androgen excess and hyperinsulinemia are key contributing features that are exacerbated by obesity. Both weight reduction and increases in physical activity are highly effective in increasing insulin sen- sitivity but underutilized in clinical practice as evidence on effective strategies to achieve this are lacking. The use of metformin is effective in restoring ovulatory function through improvement in insulin sensitivity, possi- bly also mediated by weight loss. Orlistat and sibutramine have also been shown to assist in weight loss and thereby restore reproductive function. In the morbidly obese with PCOS, bariatric surgery has been shown to achieve substantial weight loss and to be effective in improving fertility. The literature on effective diet and exercise programs for PCOS has been sparse. Studies examining the role of meal replacements as well as structured dietary patterns with higher protein composition and/or lower glycemic-index carbohydrates show promise. Further studies on novel lifestyle programs are needed compared to standard care and pharmaco- therapy to guide clinical practice.
Key Words: Polycystic ovary syndrome; weight loss; insulin resistance; lifestyle programs; metformin
.
1. INTRODUCTION
The prevalence of the different pathological conditions causing clinically evident androgen excess is largely dominated by polycystic ovary syndrome (PCOS), which represents 82% of this population (1). There is also a strong link between obesity and conditions of androgen excess such as PCOS, with half being overweight or obese. The role of weight reduction and lifestyle modification in restoring reproductive function is examined in this chapter.
2. BACKGROUND
Various studies have reported different levels of obesity, with the highest percentages being in the
Western world, including the United States, the United Kingdom, and Australia. Obesity, but also
associated menstrual disturbances, hirsutism, acne, and male pattern of alopecia, in women with
androgen excess all contribute to the poor quality of life of these patients. Furthermore, obesity is
also associated with a number of health problems, including infertility, miscarriage, adverse preg-
nancy outcomes, type 2 diabetes mellitus, hyperlipidemia, heart disease, osteoarthritis, and other
serious health outcomes. PCOS is a heterogeneous clinical syndrome characterized by
hyperandrogenism with chronic anovulation in women without specific adrenal or pituitary gland
disease. The age of onset is frequently perimenarchal, and, in some cases, premature adrenarche may be a precursor to the development of the syndrome.
2.1. Mechanism Linking Obesity and PCOS
The mechanisms linking obesity and PCOS are unclear but may be related to insulin resistance and hyperandrogenism, both of which are commonly documented in lean and obese women with this condition. Insulin resistance is a common but not universal feature of PCOS, although women with insulin resistance appear to be more clinically affected (2).
Insulin is a physiological hormone regulating ovarian function, specifically ovarian steroidogen- esis and androgen blood transport and/or activity in the target tissues (3). The high insulin levels associated with insulin resistance stimulate the ovary to make excessive amounts of androgens. Addi- tionally, high insulin levels decrease levels of sex hormone-binding globulin (SHBG), increasing the bioavailability of androgens. Moreover, high insulin levels may also work at the level of the brain, causing increased luteinizing hormone (LH) secretion, which in turn stimulates greater ovarian androgen production.
Because insulin resistance is strongly influenced by obesity in non-PCOS subjects, it was initially
debated whether insulin resistance and hyperinsulinemia are a primary metabolic disturbance of
PCOS or a symptom of the obesity commonly observed in PCOS. Hyperandrogenemia and insulin
resistance appear to be independent features of PCOS, with hyperinsulinemia enhancing the expres-
sion of hyperandrogenemia by increasing bioavailability of androgens (4) (Fig. 1). Obese women
with PCOS show decreased insulin sensitivity and hyperinsulinemia to an extent greater than can be
explained by obesity alone (4,5). A synergistic interaction appears to exist with the degree of insulin
resistance and hyperinsulinemia in lean PCOS women augmented in those who have obesity. Not all
women with PCOS exhibit hyperinsulinemia and insulin resistance, and discrepant results may be
explained by the heterogeneity and complex etiology of the syndrome. Silfen et al. (6) found a more
pronounced alteration in the hypothalamic–pituitary–adrenal axis in non-obese adolescents with
PCOS, including higher levels of LH, SHBG, androstenedione, dehydroepiandrosterone sulfate
Fig. 1. Schematic representation of how insulin resistance may contribute to the androgen excess of polycys- tic ovary syndrome (PCOS). SHBG, sex hormone-binding globulin; LH, luteinizing hormone; FSH, follicle- stimulating hormone.(DHEAS), dihydrotestosterone, and free insulin-like growth factor-1, but a more marked insulin resistance in obese adolescents with PCOS.
Hyperandrogenism is postulated to result from either or both increased adrenal and ovarian andro- gen production. The predominance of abdominal obesity, insulin resistance, glucose intolerance, hypertension, and other conditions suggests that the metabolic syndrome may be more common in PCOS, and indeed this has been reported by a number of investigators (7). It is therefore obvious that for adequate treatment of patients with androgen excess, there needs to be a reduction in hyperinsulinemia and insulin resistance as well as in obesity per se. Both weight reduction and in- creases in physical activity are highly effective in increasing insulin sensitivity. These interrelated and yet separate issues are the focus of the following discussion.
2.2. Metformin, Weight Loss, and PCOS
The initial use of metformin in the treatment of PCOS has now been widely accepted to be a valuable and inexpensive therapeutic modality. Recent systematic reviews have indicated that metformin is highly effective in inducing ovulation and increasing pregnancy rates (8,9). The num- bers needed to treat for ovulation are around four patients, and there is an improvement in serum insulin levels and a reduction in free testosterone in response to metformin. The drug appears to be safe in early pregnancy with respect to congenital abnormalities, although it is controversial whether miscarriage rates are reduced. The predictors of success of metformin have not been established, although there is some evidence that patients who are substantially overweight do not respond as well. Side effects of metformin include nausea, vomiting, diarrhea, and other forms of gastrointesti- nal intolerance, and patients need to be warned about the interaction between metformin and alcohol.
The ovulatory response to clomiphene can be increased in obese women with PCOS by decreasing insulin secretion with metformin (10). The role of metformin in weight loss is controversial with a number of studies showing some weight loss and others showing no change at all. The National Institute of Child Health and Human Development’s Reproductive Medicine Network has begun a randomized, double-blind trial of clomiphene vs metformin vs clomiphene plus metformin for the induction of ovulation in patients with PCOS seeking pregnancy, with live-birth rate as the primary outcome (11). This trial should definitively answer the question of the relative efficacy of metformin, clomiphene, and combination therapy in the treatment of infertile women with PCOS.
One of the best studies relating to metformin use in androgen excess was that by Pasquali et al.
(12). They randomized patients with PCOS or obesity alone who were weight index-matched to a lifestyle-modification program including diet plus metformin or placebo. After 6 months the fre- quency of menstrual cycles was better with metformin, and metformin was superior to placebo alone in the loss of weight, reduction in waist circumference and visceral fat, and reduction in testosterone.
There was no differential benefit of metformin on fasting serum glucose, insulin, or SHBG. Patients with androgen excess responded better than matched patients with obesity to metformin with respect to reduction of visceral fat and testosterone, but not in terms of weight loss, weight circumference, fasting serum glucose, or insulin.
This suggests that the addition of metformin to lifestyle modification may be of some benefit to all
obese subjects in terms of weight loss and reduction of central fat, particularly so for PCOS patients
with regard to central fat. Whether this is a direct effect of metformin alone or indirect through the
contribution of gastrointestinal side effects remains to be verified. Weight loss (3.9 kg after 8 months)
is a feature of protracted metformin therapy (1.5 g/day) in obese women with PCOS, with greater
weight reduction potentially achievable with higher doses (1.50 or 2.55 g/day) (13). No dose-
response effect in weight loss was noted in the morbidly obese with PCOS, and there was no dose-
response effect with reductions in androstenedione, which was significant with both doses. Systematic
reviews of metformin’s effect on weight loss do not suggest that this trend can be generalized beyond
PCOS. Given the relatively fewer side effects of metformin, there would appear to be no harm in
using metformin as part of a weight loss program in patients with PCOS. At present, however,
metformin should probably be stopped as soon as pregnancy is established. Alcohol should be avoided, and the very rare occurrence of lactic acidosis should be borne in mind.
It is likely that weight reduction plays the most significant role in restoration of ovulation in obese women with PCOS and that this may be the primary mechanism for the effects noted with metformin, independent of its insulin-sensitizing effects (14). More recently, drugs that target weight loss have been compared with metformin therapy in women with PCOS. Treatment with orlistat for 3 months led to a 4.7% reduction in body weight, a more significant loss than was observed in metformin- treated women (1.0%). Serum testosterone levels declined significantly in both groups with no change in levels of SHBG. This agent has potential as an adjunct to the treatment of PCOS (15).
The effects of metformin (1700 mg/day) vs acarbose (300 mg/day) on insulin resistance, hormone profiles, and ovulation rates in patients with clomiphene citrate-resistant PCOS have recently been assessed (16). The ratio of LH to follicle-stimulating hormone (FSH) and total testosterone concen- trations decreased and ovulation rates increased in both groups. Reduction in weight and body mass index (BMI) was only significant in the acarbose group.
In a placebo-controlled, double-blind study, Tang et al. (17) randomized 143 oligo-/amenorrheic obese women with PCOS to metformin (850 mg) or placebo twice daily for 6 months. All received diet and lifestyle advice from a dietitian. Both groups showed significant improvements in menstrual frequency and weight loss, with no significant differences between the groups. Logistic regression analysis showed that only percentage weight loss correlated with an improvement in menses. Women who received metformin achieved a significant reduction in waist circumference and free androgen index (FAI). Because this is one of the largest such studies conducted, it suggests that metformin does not improve weight loss or menstrual frequency in obese patients with PCOS receiving weight- management advice and that weight loss alone through lifestyle changes, if this can be achieved, can significantly improve menstrual frequency.
The benefits of weight reduction in women with androgen excess and PCOS are well documented.
In overweight women with hyperandrogenism and PCOS, weight loss decreases abdominal fat, hyperandrogenism, and insulin resistance and improves lipid profiles, menstrual cyclicity, and fertil- ity and risk factors for diabetes and cardiovascular disease (18–21). An important point is that a minimal amount of weight loss is sufficient to improve the presentation of PCOS. A moderate weight loss of 5% initial body weight on an energy-restricted diet results in reduction in insulin concentra- tions, reciprocal changes in SHBG, and improved menstrual cyclicity and fertility in the majority of patients (21). In this study a reduction in hirsutism was also noted in 40% of women.
Moran et al. have (20) also confirmed that a 7.5% weight loss in overweight women with PCOS increases SHBG, decreases the FAI and testosterone, and improves menstrual cyclicity, and that this can occur as soon as within the first 4 weeks of energy restriction and be sustained through weight loss. Energy restriction and weight loss is thus a desirable outcome in overweight women with PCOS for short- and long-term improvements in reproductive and metabolic health.
Replacing protein for carbohydrate within the context of an energy-restricted diet was not associ- ated with significant differences in reproductive outcomes, although postprandial glucose response was 3.5-fold lower on the higher protein dietary pattern. No changes in hirsutism were noted (20).
High concentrations of serum LH in the follicular phase are associated with PCOS and with decreased reproductive function (22). Tonic hypersecretion of LH appears to induce premature oocyte maturation, causing problems with fertilization and miscarriage. Van Dam et al. (23) noted that 7 days of calorie restriction on a very-low-calorie diet (VLCD) (471 kcal/day) paradoxically increased basal and pul- satile LH secretion, despite reductions in plasma glucose, insulin, leptin, and testosterone concentra- tions, which decreased by 18, 75, 50, and 23%, respectively. Serum estrone, estradiol, SHBG, and androstenedione concentrations remained unchanged.
Van Dam et al. (24) examined predictors of improvements in ovarian function in response to a
6-month weight loss, noting that responders exhibited a significant decline of circulating estradiol con-
centrations and a concurrent increase in LH secretion in response to 7 days of acute energy restriction
using a VLCD, whereas neither parameter changed significantly in nonresponders. The authors sug- gest that this hormonal response to energy restriction may be a marker or precedent for follicle matu- ration and ovulation in these patients. It is concluded that in PCOS women receiving long-term downregulation and stimulation with recombinant FSH, insulin resistance is related to neither hor- mone levels nor the outcome of in vitro fertilization. Obesity, independent of insulin resistance, is associated with relative gonadotropin resistance (25).
2.4. Dietary Composition and Weight Management
Although low-fat, high-carbohydrate diets have been the mainstream approach for weight man- agement, they appear to be no more effective than other dietary patterns that restrict kilojoules (26).
Furthermore, high-carbohydrate dietary patterns may worsen the metabolic profile if weight loss is not achieved. Modifying the type of dietary carbohydrate or glycemic index (GI) has been highly controversial (27,28). GI is proposed to both improve the cardiovascular risk profile and aid in weight loss (29,30), although education on GI has not shown an improvement in weight loss at 10 weeks (31) or 1 year (32). Surprisingly, there appear to be no studies on the utility of using GI as a strategy for weight management in women PCOS. Increasing the amount of dietary protein at the expense of carbohydrate has been shown to reduce abdominal fat in insulin-resistant subjects (33,34) and has been shown to be more effective in improving weight loss after 6 months and 1 year (35,36). How- ever, in two small studies in PCOS subjects, no differential effect of protein was observed (20,37), although these dietary studies were not ad libitum. Improvements in postprandial glucose response were noted on the higher protein pattern. A proposed mechanism whereby protein is thought to exert effects on weight management is through increased satiety (38). This could be advantageous, as it has been shown that satiety appears impaired in women with PCOS (39).
PCOS is frequently associated with morbid obesity, in which conventional lifestyle modification may present a challenge. Sustained and marked weight loss has been achieved by bariatric surgery (40). A weight loss of 41 kg after 12 months was paralleled by a decrease in the hirsutism score and free testosterone, androstendione, and DHEAS and the restoration of regular menstrual cycles and/or ovulation in all patients. There is some indication that weight loss studies in women with PCOS have increased drop-out rates: 26–38% over 1–4 months (20,37) and 8–9% over 4 months in non-PCOS subjects (33,38). This may be a result of the increased difficulty of energy restriction consequent to lower satiety (41).
The use of alternative dietary compositions provides patients with an increased range of dietary options and may be more successful for optimally improving the metabolic profile and achieving and sustaining a reduced weight. However, continued follow-up is required to sustain weight loss, as this is likely to outweigh the effects of dietary composition (42).
Meal replacements have been shown to be an effective weight loss strategy in overweight women with PCOS. Moran et al. (43) placed 34 overweight women with PCOS on a weight-loss intervention (two meal replacements, low-fat snacks, and evening meal daily) for 8 weeks and reviewed them every 2 weeks (Fig. 2). The intervention resulted in a 5.6-kg (6%) reduction in weight and a 6-cm reduction in waist circumference. There was no change in SHBG, but a significant reduction in serum testosterone (0.3 r 0.7 nmol/L) and FAI (3.1 r4. 6nmol/L, 16.8%). This change in FAI occurred from weeks 0 to 2 and corresponded with a weight loss of 2.4 r 1.0 kg (2.5%), with no further changes in FAI occurring from weeks 2 to 8. These data suggest that reproductive function can be restored very quickly by acute energy restriction. The implication is that only short-term energy restriction may be required to improve reproductive function and that weight loss is needed to sustain it, but this requires further investigation.
2.5. Physical Activity, Insulin Sensitivity, and Hormonal Control
Despite the considerable evidence that physical activity provides an effective medium for improv-
ing insulin sensitivity in a wide range of insulin-resistant states, the potential benefits of exercise for
improving hormonal and metabolic abnormalities in individuals with hyperandrogenism is not well understood. To date, only two controlled studies have examined the direct effects of physical exer- cise in women with excessive androgen levels (44,45). In 2002 Randeva et al. (44) showed no effects of a 6-month exercise program on either fasting insulin or FAI in young overweight and obese women with PCOS. However, baseline levels of insulin resistance were relatively low in their subjects, and this study only evaluated the effects of light aerobic exercise, which could have limited the changes observed. Jaatinen (45) challenged nine oligomenorrheic women with PCOS (BMI 19.5–46.0 kg/m
2) and eight control women with regular menstrual cycles (BMI 20.0–53.5 kg/m
2) with a bicycle ergo- meter test. The exercise-induced increase in circulating growth hormone levels was significantly greater in controls than in PCOS patients. There was also a negative correlation between the growth hormone response and BMI. The increases in the concentrations of adrenaline, noradrenaline, 3,4- dihydroxyphenylglycol, glucose, and insulin:C-peptide ratios during the bicycle ergometer test were correlated negatively to BMI. The authors concluded that obesity is an important determinant of the hormonal responses to physical exercise.
Further research is required to examine hormonal adaptations to exercise training and to evaluate the role of differing forms and duration of exercise for optimizing management of metabolic and hormonal abnormalities in populations with excess androgen levels. Equally important is the assess- ment of compliance to exercise regimes and strategies to optimize this. The possible interactions between insulin and testosterone in response to exercise therapies also warrant further study. There is little doubt that exercise provides a means of increasing energy expenditure and plays a pivotal role in management and that a dose-response effect exists, such that more exercise is associated with greater weight loss and maintenance.
3. CONCLUSION
Both weight reduction and increases in physical activity are highly effective in increasing insulin sensitivity and restoring reproductive function in PCOS. The use of metformin is effective in restor- ing ovulatory function through improvement in insulin sensitivity, possibly also mediated by weight loss. Orlistat and sibutramine have also been shown to assist in weight loss and thereby restore repro- ductive function. In the morbidly obese with PCOS, bariatric surgery has been shown achieve sub- stantial weight loss and improve fertility.
Fig. 2. Effects of short-term weight loss using meal replacements two times daily plus snacks plus low-fat meal; dietary intake/day 4904 kJ, composed of 21% fat, 24% protein, 53% carbohydrate—on insulin and free androgen index in polycystic ovary syndrome (PCOS). *p < 0.01 from baseline. (Adapted from ref. 43.)
The literature on effective diet and exercise programs for PCOS has been sparse compared with studies evaluating the role of pharmaceutical agents. Hence, lifestyle management has been underutilized in clinical management. Studies examining the role of meal replacements as well as structured dietary patterns with higher protein composition and/or lower glycemic index carbohy- drates show promise, but further studies on novel lifestyle programs are needed compared to standard care and pharmacotherapy to guide clinical practice.
4. FUTURE AVENUES OF INVESTIGATION
The role of diet composition in PCOS needs further study. In particular, the utility of the gas- trointestinal system in assisting energy restriction in PCOS needs to be assessed, as does the effect of high-protein and low-carbohydrate diets on satiety in this group. More data on the type and intensity of physical activity required to improve reproductive performance is needed. Whether this is modi- fied by a concomitant energy-restricted diet will guide the development of well-defined lifestyle- intervention programs. These programs need to be tailored to PCOS patients and evaluated against and in addition to metformin. Understanding the motivation of responders and nonresponders to lifestyle intervention, both behavioral and metabolic, will also assist in tailoring clinical management of PCOS.
KEY POINTS
• PCOS is a significant cause of infertility and is related to excess androgen production and insulin resis- tance compounded by obesity.
• Weight loss and physical activity can significantly improve the reproductive milieu, with improvements noted within 2 weeks of introduction.
• Metformin is commonly used to improve insulin sensitivity mediated in part by a small weight loss.
• Structured dietary patterns with higher protein composition and/or lower glycemic index carbohydrates show promise, as does the use of meal replacements.
• Lifestyle programs incorporating weight management and physical activity can be as effective as pharma- cotherapy, but have been underutilized in clinical management.
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